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Hägglöf, Christina
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Publications (10 of 16) Show all publications
Hammarsten, P., Josefsson, A., Thysell, E., Lundholm, M., Hägglöf, C., Iglesias-Gato, D., . . . Bergh, A. (2019). Immunoreactivity for prostate specific antigen and Ki67 differentiates subgroups of prostate cancer related to outcome. Modern Pathology, 32(9), 1310-1319
Open this publication in new window or tab >>Immunoreactivity for prostate specific antigen and Ki67 differentiates subgroups of prostate cancer related to outcome
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2019 (English)In: Modern Pathology, ISSN 0893-3952, E-ISSN 1530-0285, Vol. 32, no 9, p. 1310-1319Article in journal (Refereed) Published
Abstract [en]

Based on gene-expression profiles, prostate tumors can be subdivided into subtypes with different aggressiveness and response to treatment. We investigated if similar clinically relevant subgroups can be identified simply by the combination of two immunohistochemistry markers: one for tumor cell differentiation (prostate specific antigen, PSA) and one for proliferation (Ki67). This was analyzed in men with prostate cancer diagnosed at transurethral resection of the prostate 1975-1991 (n = 331) where the majority was managed by watchful waiting. Ki67 and PSA immunoreactivity was related to outcome and to tumor characteristics previously associated with prognosis. Increased Ki67 and decreased PSA were associated with poor outcome, and they provided independent prognostic information from Gleason score. A combinatory score for PSA and Ki67 immunoreactivity was produced using the median PSA and Ki67 levels as cut-off (for Ki67 the upper quartile was also evaluated) for differentiation into subgroups. Patients with PSA low/Ki67 high tumors showed higher Gleason score, more advanced tumor stage, and higher risk of prostate cancer death compared to other patients. Their tumor epithelial cells were often ERG positive and expressed higher levels of ErbB2, phosphorylated epidermal growth factor receptor (pEGF-R) and protein kinase B (pAkt), and their tumor stroma showed a reactive response with type 2 macrophage infiltration, high density of blood vessels and hyaluronic acid, and with reduced levels of caveolin-1, androgen receptors, and mast cells. In contrast, men with PSA high/Ki67 low tumors were characterized by low Gleason score, and the most favorable outcome amongst PSA/Ki67-defined subgroups. Men with PSA low/Ki67 low tumors showed clinical and tumor characteristics intermediate of the two groups above. A combinatory PSA/Ki67 immunoreactivity score identifies subgroups of prostate cancers with different epithelial and stroma phenotypes and highly different outcome but the clinical usefulness of this approach needs to be validated in other cohorts.

National Category
Urology and Nephrology
Identifiers
urn:nbn:se:umu:diva-163898 (URN)10.1038/s41379-019-0260-6 (DOI)000484437000009 ()30980038 (PubMedID)2-s2.0-85064215051 (Scopus ID)
Available from: 2019-10-07 Created: 2019-10-07 Last updated: 2019-11-14Bibliographically approved
Adamo, H. H., Hammarsten, P., Hägglöf, C., Scherdin, T. D., Egevad, L., Stattin, P., . . . Bergh, A. (2019). Prostate cancer induces C/EBP expression in surrounding epithelial cells which relates to tumor aggressiveness and patient outcome. The Prostate, 79(5)
Open this publication in new window or tab >>Prostate cancer induces C/EBP expression in surrounding epithelial cells which relates to tumor aggressiveness and patient outcome
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2019 (English)In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 79, no 5Article in journal (Refereed) Published
Abstract [en]

Background: Implantation of rat prostate cancer cells into the normal rat prostate results in tumor-stimulating adaptations in the tumor-bearing organ. Similar changes are seen in prostate cancer patients and they are related to outcome. One gene previously found to be upregulated in the non-malignant part of tumor-bearing prostate lobe in rats was the transcription factor CCAAT/enhancer-binding protein- (C/EBP).

Methods: To explore this further, we examined C/EBP expression by quantitative RT-PCR, immunohistochemistry, and Western blot in normal rat prostate tissue surrounding slow-growing non-metastatic Dunning G, rapidly growing poorly metastatic (AT-1), and rapidly growing highly metastatic (MatLyLu) rat prostate tumors?and also by immunohistochemistry in a tissue microarray (TMA) from prostate cancer patients managed by watchful waiting.

Results: In rats, C/EBP mRNA expression was upregulated in the surrounding tumor-bearing prostate lobe. In tumors and in the surrounding non-malignant prostate tissue, C/EBP was detected by immunohistochemistry in some epithelial cells and in infiltrating macrophages. The magnitude of glandular epithelial C/EBP expression in the tumor-bearing prostates was associated with tumor size, distance to the tumor, and metastatic capacity. In prostate cancer patients, high expression of C/EBP in glandular epithelial cells in the surrounding tumor-bearing tissue was associated with accumulation of M1 macrophages (iNOS+) and favorable outcome. High expression of C/EBP in tumor epithelial cells was associated with high Gleason score, high tumor cell proliferation, metastases, and poor outcome.

Conclusions: This study suggest that the expression of C/EBP-beta, a transcription factor mediating multiple biological effects, is differentially expressed both in the benign parts of the tumor-bearing prostate and in prostate tumors, and that alterations in this may be related to patient outcome.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019
Keywords
biomarkers, C, EBP, prostate cancer, tumors instruct adjacent tissues
National Category
Cancer and Oncology Urology and Nephrology
Identifiers
urn:nbn:se:umu:diva-157947 (URN)10.1002/pros.23749 (DOI)000461573200001 ()30536410 (PubMedID)
Available from: 2019-04-17 Created: 2019-04-17 Last updated: 2019-04-17Bibliographically approved
Halin Bergström, S., Hägglöf, C., Thysell, E., Bergh, A., Wikström, P. & Lundholm, M. (2016). Extracellular Vesicles from Metastatic Rat Prostate Tumors Prime the Normal Prostate Tissue to Facilitate Tumor Growth. Scientific Reports, 6, Article ID 31805.
Open this publication in new window or tab >>Extracellular Vesicles from Metastatic Rat Prostate Tumors Prime the Normal Prostate Tissue to Facilitate Tumor Growth
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2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 31805Article in journal (Refereed) Published
Abstract [en]

Accumulating data indicates that tumor-derived extracellular vesicles (EVs) are responsible for tumor-promoting effects. However, if tumor EVs also prepare the tumor-bearing organ for subsequent tumor growth, and if this effect is different in low and high malignant tumors is not thoroughly explored. Here we used orthotopic rat Dunning R-3327 prostate tumors to compare the role of EVs from fast growing and metastatic MatLyLu (MLL) tumors with EVs from more indolent and non-metastatic Dunning G (G) tumors. Prostate tissue pre-conditioned with MLL-EVs in vivo facilitated G tumor establishment compared to G-EVs. MLL-EVs increased prostate epithelial proliferation and macrophage infiltration into the prostate compared to G-EVs. Both types of EVs increased macrophage endocytosis and the mRNA expression of genes associated with M2 polarization in vitro, with MLL-EVs giving the most pronounced effects. MLL-EVs also altered the mRNA expression of growth factors and cytokines in primary rat prostate fibroblasts compared to G-EVs, suggesting fibroblast activation. Our findings propose that EVs from metastatic tumors have the ability to prime the prostate tissue and enhance tumor growth to a higher extent than EVs from non-metastatic tumors. Identifying these differences could lead to novel therapeutic targets and potential prognostic markers for prostate cancer.

Place, publisher, year, edition, pages
Nature Publishing Group, 2016
National Category
Cancer and Oncology Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-125538 (URN)10.1038/srep31805 (DOI)000381757500001 ()
Available from: 2016-09-19 Created: 2016-09-13 Last updated: 2018-06-07Bibliographically approved
Hammarsten, P., Scherdin, T. D., Hagglöf, C., Andersson, P., Wikström, P., Stattin, P., . . . Bergh, A. (2016). High Caveolin-1 Expression in Tumor Stroma Is Associated with a Favourable Outcome in Prostate Cancer Patients Managed by Watchful Waiting. PLoS ONE, 11(10), Article ID e0164016.
Open this publication in new window or tab >>High Caveolin-1 Expression in Tumor Stroma Is Associated with a Favourable Outcome in Prostate Cancer Patients Managed by Watchful Waiting
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2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 10, article id e0164016Article in journal (Refereed) Published
Abstract [en]

In the present study we have investigated whether Caveolin-1 expression in non-malignant and malignant prostate tissue is a potential prognostic marker for outcome in prostate cancer patients managed by watchful waiting. Caveolin-1 was measured in prostate tissues obtained through transurethral resection of the prostate from 395 patients diagnosed with prostate cancer. The majority of the patients (n = 298) were followed by watchful waiting after diagnosis. Tissue microarrays constructed from malignant and non-malignant prostate tissue were stained with an antibody against Caveolin-1. The staining pattern was scored and related to clinicopathologic parameters and outcome. Microdissection and qRT-PCR analysis of Cav-1 was done of the prostate stroma from non-malignant tissue and stroma from Gleason 3 and 4 tumors. Cav-1 RNA expression was highest in non-malignant tissue and decreased during cancer progression. High expression of Caveolin-1 in tumor stroma was associated with significantly longer cancer specific survival in prostate cancer patients. This association remained significant when Gleason score and local tumor stage were combined with Caveolin-1 in a Cox regression model. High stromal Caveolin-1 immunoreactivity in prostate tumors is associated with a favourable prognosis in prostate cancer patients managed by watchful waiting. Caveolin-1 could possibly become a useful prognostic marker for prostate cancer patients that are potential candidates for active surveillance.

National Category
Urology and Nephrology Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-127714 (URN)10.1371/journal.pone.0164016 (DOI)000386204500015 ()27764093 (PubMedID)
Available from: 2016-12-15 Created: 2016-11-18 Last updated: 2018-06-09Bibliographically approved
Iglesias-Gato, D., Wikström, P., Tyanova, S., Lavallee, C., Thysell, E., Carlsson, J., . . . Flores-Morales, A. (2016). The Proteome of Primary Prostate Cancer. European Urology, 69(5), 942-952
Open this publication in new window or tab >>The Proteome of Primary Prostate Cancer
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2016 (English)In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 69, no 5, p. 942-952Article in journal (Refereed) Published
Abstract [en]

Background: Clinical management of the prostate needs improved prognostic tests and treatment strategies. Because proteins are the ultimate effectors of most cellular reactions, are targets for drug actions and constitute potential biomarkers; a quantitative systemic overview of the proteome changes occurring during prostate cancer (PCa) initiation and progression can result in clinically relevant discoveries. Objectives: To study cellular processes altered in PCa using system-wide quantitative analysis of changes in protein expression in clinical samples and to identify prognostic biomarkers for disease aggressiveness. Design, setting, and participants: Mass spectrometry was used for genome-scale quantitative proteomic profiling of 28 prostate tumors (Gleason score 6-9) and neighboring nonmalignant tissue in eight cases, obtained from formalin-fixed paraffin-embedded prostatectomy samples. Two independent cohorts of PCa patients (summing 752 cases) managed by expectancy were used for immunohistochemical evaluation of proneuropeptide-Y (pro-NPY) as a prognostic biomarker. Results and limitations: Over 9000 proteins were identified as expressed in the human prostate. Tumor tissue exhibited elevated expression of proteins involved in multiple anabolic processes including fatty acid and protein synthesis, ribosomal biogenesis and protein secretion but no overt evidence of increased proliferation was observed. Tumors also showed increased levels of mitochondrial proteins, which was associated with elevated oxidative phosphorylation capacity measured in situ. Molecular analysis indicated that some of the proteins overexpressed in tumors, such as carnitine palmitoyltransferase 2 (CPT2, fatty acid transporter), coatomer protein complex, subunit alpha (COPA, vesicle secretion), and mitogen-and stress-activated protein kinase 1 and 2 (MSK1/2, protein kinase) regulate the proliferation of PCa cells. Additionally, pro-NPY was found overexpressed in PCa (5-fold, p < 0.05), but largely absent in other solid tumor types. Pro-NPY expression, alone or in combination with the ERG status of the tumor, was associated with an increased risk of PCa specific mortality, especially in patients with Gleason score <= 7 tumors. Conclusions: This study represents the first system-wide quantitative analysis of proteome changes associated to localized prostate cancer and as such constitutes a valuable resource for understanding the complex metabolic changes occurring in this disease. We also demonstrated that pro-NPY, a protein that showed differential expression between high and low risk tumors in our proteomic analysis, is also a PCa specific prognostic biomarker associated with increased risk for disease specific death in patients carrying low risk tumors. Patient summary: The identification of proteins whose expression change in prostate cancer provides novel mechanistic information related to the disease etiology. We hope that future studies will prove the value of this proteome dataset for development of novel therapies and biomarkers. 

Keywords
Prostate cancer, Quantitative proteomics, Formalin-fixed paraffin-embedded, Proneuropeptide-Y, tchful waiting
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-120358 (URN)10.1016/j.eururo.2015.10.053 (DOI)000374171700037 ()26651926 (PubMedID)
Available from: 2016-05-20 Created: 2016-05-16 Last updated: 2018-06-07Bibliographically approved
Nilsson, M., Hägglöf, C., Hammarsten, P., Thysell, E., Stattin, P., Egevad, L., . . . Bergh, A. (2015). High Lysyl Oxidase (LOX) in the Non-Malignant Prostate Epithelium Predicts a Poor Outcome in Prostate Cancer Patient Managed by Watchful Waiting. PLoS ONE, 10(10), Article ID e0140985.
Open this publication in new window or tab >>High Lysyl Oxidase (LOX) in the Non-Malignant Prostate Epithelium Predicts a Poor Outcome in Prostate Cancer Patient Managed by Watchful Waiting
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2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 10, article id e0140985Article in journal (Refereed) Published
Abstract [en]

Lysyl oxidase (LOX) has been shown to both promote and suppress tumor progression, but its role in prostate cancer is largely unknown. LOX immunoreactivity was scored in prostate tumor epithelium, tumor stroma and in the tumor-adjacent non-malignant prostate epithelium and stroma. LOX scores in tumor and non-malignant prostate tissues were then examined for possible associations with clinical characteristics and survival in a historical cohort of men that were diagnosed with prostate cancer at transurethral resection and followed by watchful waiting. Men with a low LOX score in the non-malignant prostate epithelium had significantly longer cancer specific survival than men with a high score. Furthermore, LOX score in non-malignant prostate epithelium remained prognostic in a multivariable analysis including Gleason score. LOX score in prostate tumor epithelium positively correlated to Gleason score and metastases but was not associated with cancer survival. LOX score in tumor and non-malignant prostate stroma appeared unrelated to these tumor characteristics. In radical prostatectomy specimens, LOX immune-staining corresponded to LOX in-situ hybridization and LOX mRNA levels were found to be similar between tumor and adjacent non-malignant areas, but significantly increased in bone metastases samples. LOX levels both in tumors and in the surrounding tumor-bearing organ are apparently related to prostate cancer aggressiveness.

Place, publisher, year, edition, pages
Public library science, 2015
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-112009 (URN)10.1371/journal.pone.0140985 (DOI)000363799900020 ()26501565 (PubMedID)
Available from: 2015-11-30 Created: 2015-11-30 Last updated: 2018-06-07Bibliographically approved
Lundholm, M., Hägglöf, C., Wikberg, M. L., Stattin, P., Egevad, L., Bergh, A., . . . Edin, S. (2015). Secreted Factors from Colorectal and Prostate Cancer Cells Skew the Immune Response in Opposite Directions. Scientific Reports, 5, Article ID 15651.
Open this publication in new window or tab >>Secreted Factors from Colorectal and Prostate Cancer Cells Skew the Immune Response in Opposite Directions
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2015 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 15651Article in journal (Refereed) Published
Abstract [en]

Macrophage infiltration has been associated with an improved prognosis in patients with colorectal cancer (CRC), but a poor prognosis in prostate cancer (PC) patients. In this study, the distribution and prognostic value of proinflammatory M1 macrophages (NOS2(+)) and immunosuppressive M2 macrophages (CD163(+)) was evaluated in a cohort of 234 PC patients. We found that macrophages infiltrating PC were mainly of an M2 type and correlated with a more aggressive tumor and poor patient prognosis. Furthermore, the M1/M2 ratio was significantly decreased in PC compared to CRC. Using in vitro cell culture experiments, we could show that factors secreted from CRC and PC cells induced macrophages of a proinflammatory or immunosuppressive phenotype, respectively. These macrophages differentially affected autologous T lymphocyte proliferation and activation. Consistent with this, CRC specimens were found to have higher degrees of infiltrating T-helper 1 cells and active cytotoxic T lymphocytes, while PC specimens displayed functionally inactive T cells. In conclusion, our results imply that tumour-secreted factors from cancers of different origin can drive macrophage differentiation in opposite directions and thereby regulate the organization of the anti-tumour immune response. Our findings suggest that reprogramming of macrophages could be an important tool in the development of new immunotherapeutic strategies.

Place, publisher, year, edition, pages
Nature Publishing Group, 2015
National Category
Medical Bioscience
Identifiers
urn:nbn:se:umu:diva-111473 (URN)10.1038/srep15651 (DOI)000363445900002 ()26503803 (PubMedID)
Available from: 2015-12-07 Created: 2015-11-13 Last updated: 2018-06-07Bibliographically approved
Tidehag, V., Hammarsten, P., Egevad, L., Grantors, T., Stattin, P., Leanderson, T., . . . Bergh, A. (2014). High density of S100A9 positive inflammatory cells in prostate cancer stroma is associated with poor outcome. European Journal of Cancer, 50(10), 1829-1835
Open this publication in new window or tab >>High density of S100A9 positive inflammatory cells in prostate cancer stroma is associated with poor outcome
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2014 (English)In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 50, no 10, p. 1829-1835Article in journal (Refereed) Published
Abstract [en]

Purpose: To elucidate if the density of inflammatory cells expressing S100A9 in malignant and surrounding non-malignant prostate tissues is a prognostic marker for outcome in prostate cancer patients. Experimental design: Tissue was obtained from 358 men diagnosed with prostate cancer at transurethral resection of the prostate due to obstructive voiding problems, of which 260 were then followed with watchful waiting. Tissue microarrays of both malignant and non-malignant tissues were stained with an antibody against S100A9. The number of stained inflammatory cells was scored and related to clinical outcome and histopathological parameters of known prognostic value. Results: A high number of inflammatory cells expressing S100A9 in both malignant and surrounding non-malignant tissues were associated with significantly shorter cancer-specific survival. This association remained significant when Gleason score and local tumour stage were analysed together with S100A9 in a Cox regression model. Low number of S100A9 positive cells in non-malignant stroma was correlated to significantly longer cancer-specific survival also in patients with Gleason score 8-10 tumours. S100A9 positive cells in tumour stroma were correlated with Gleason score, hyaluronan, platelet-derived growth factor receptor beta (PDGFR-beta), and androgen receptor (inverse correlation) in tumour stroma. S100A9 positive cells in non-malignant stroma correlated with androgen receptor in this tissue compartment (inverse correlation). Conclusions: A high number of S100A9 positive inflammatory cells in tumour stroma and in non-malignant stroma were associated with shorter cancer-specific survival in prostate cancer patients.

Keywords
Prostate cancer, S100A9, Prognostic marker, Watchful waiting
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-91261 (URN)10.1016/j.ejca.2014.03.278 (DOI)000337875800016 ()
Available from: 2014-07-30 Created: 2014-07-28 Last updated: 2018-06-07Bibliographically approved
Bruzzese, F., Hägglöf, C., Leone, A., Sjöberg, E., Roca, M. S., Kiflemariam, S., . . . Augsten, M. (2014). Local and systemic protumorigenic effects of cancer-associated fibroblast-derived GDF15. Cancer Research, 74(13), 3408-3417
Open this publication in new window or tab >>Local and systemic protumorigenic effects of cancer-associated fibroblast-derived GDF15
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2014 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 13, p. 3408-3417Article in journal (Refereed) Published
Abstract [en]

The tumor stroma is vital to tumor development, progression, and metastasis. Cancer-associated fibroblasts (CAF) are among the abundant cell types in the tumor stroma, but the range of their contributions to cancer pathogenicity has yet to be fully understood. Here, we report a critical role for upregulation of the TGF beta/BMP family member GDF15 (MIC-1) in tumor stroma. GDF15 was found upregulated in situ and in primary cultures of CAF from prostate cancer. Ectopic expression of GDF15 in fibroblasts produced prominent paracrine effects on prostate cancer cell migration, invasion, and tumor growth. Notably, GDF15-expressing fibroblasts exerted systemic in vivo effects on the outgrowth of distant and otherwise indolent prostate cancer cells. Our findings identify tumor stromal cells as a novel source of GDF15 in human prostate cancer and illustrate a systemic mechanism of cancer progression driven by the tumor microenvironment. Further, they provide a functional basis to understand GDF15 as a biomarker of poor prognosis and a candidate therapeutic target in prostate cancer. (C)2014 AACR.

Place, publisher, year, edition, pages
American Association for Cancer Research, 2014
Keywords
macrophage-inhibitory cytokine-1; prostate-cancer; growth-factor; tumor-growth; colorectal-cancer; h6d polymorphism; autocrine factor; stromal cells; expression; beta
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-91752 (URN)10.1158/0008-5472.CAN-13-2259 (DOI)000338341700005 ()
Available from: 2014-08-19 Created: 2014-08-15 Last updated: 2018-06-07Bibliographically approved
Hägglöf, C., Hammarsten, P., Strömvall, K., Egevad, L., Josefsson, A., Stattin, P., . . . Bergh, A. (2014). TMPRSS2-ERG Expression Predicts Prostate Cancer Survival and Associates with Stromal Biomarkers. PLoS ONE, 9(2), e86824
Open this publication in new window or tab >>TMPRSS2-ERG Expression Predicts Prostate Cancer Survival and Associates with Stromal Biomarkers
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2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 2, p. e86824-Article in journal (Refereed) Published
Abstract [en]

The TMPRSS2-ERG gene fusion is found in approximately half of all prostate cancers. The functional and prognostic significance of TMPRSS2-ERG is, however, not fully understood. Based on a historical watchful waiting cohort, an association between TMPRSS2-ERG, evaluated as positive immune staining, and shorter survival of prostate cancer patients was identified. Expression of ERG was also associated with clinical markers such as advanced tumor stage, high Gleason score, presence of metastasis and prognostic tumor cell markers such as high Ki67, pEGFR and pAkt. Novel associations between TMPRSS2-ERG and alterations in the tumor stroma, for example, increased vascular density, hyaluronan and PDGFR beta and decreased Caveolin-1, all known to be associated with an aggressive disease, were found. The present study suggests that the TMPRSS2-ERG fusion gene is associated with a more aggressive prostate cancer phenotype, supported by changes in the tumor stroma.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-87026 (URN)10.1371/journal.pone.0086824 (DOI)000330829200028 ()
Available from: 2014-04-07 Created: 2014-03-18 Last updated: 2018-06-08Bibliographically approved
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